Growth factors such as insulin, the epidermal growth factor and the platelet-derived growth factor (hereinafter referred to as PDGF) have an important role in cell growth. In particular, PDGF is known to be a powerful cell growth factor related to the control of cell growth and division (Cell 46, 155 (1986)). However, in diseases or pathophysiological situations such as leukemia, cancers, psoriasis, glomerular nephritis, organofibrosis, atherosclerosis, restenosis after percutaneous coronary angioplasty or bypass surgery and rheumatoid arthritis, abnormal production of PDGF or PDGF receptor occurs at the pathophysiological sites, and abnormal cell growth is observed at the pathophysiological sites in such diseases. Namely, this is an excess of cell growth signals associated with overproduction of the PDGF or PDGF receptors. Thus, it is necessary to suppress cell growth signal transduction to improve these pathophysiological situations.
In one trial, it was reported that abnormal cell growth in pathophysiological situations was suppressed by administration of an anti-PDGF antibody (J. Exp. Med. 175, 1413 (1992)); however, there are problems such as in vivo stability and methods of administration as a therapeutic agent because the anti-PDGF antibody is a protein molecule.
On the other hand, in cells, PDGF is known to bind to the PDGF receptor to activate tyrosine kinase present in this receptor. This receptor tyrosine kinase relates to intracellular signal transduction via autophosphorylation of the receptor itself and plays an important role in cell growth. In pathophysiological situations, this intracellular signal transduction is considered to be excessive. Therefore, inhibition of PDGF receptor autophosphorylation can be considered as another possible strategy to suppress cell growth signal transduction.
Examples of suppressing cell growth using the PDGF receptor autophosphorylation inhibitors, which are low molecular weight compounds, are described in the literature (Cancer Research 54, 6106 (1994); Proc. Natl. Acad. Sci. USA. 92, 2558 (1995)). Therefore, PDGF receptor autophosphorylation inhibitors could be useful in many diseases such as leukemia, cancers, psoriasis, glomerular nephritis, organofibrosis, atherosclerosis, restenosis after percutaneous coronary angioplasty or bypass surgery and rheumatoid arthritis.
Examples of previously known PDGF receptor autophosphorylation inhibitors include 3-arylquinolines (J. Med. Chem. 37, 2627 (1994); J. Med. Chem. 37, 2129 (1994) and Publication of Japanese Patent Laid-open No. 94/507643), 3-arylquinoxalines (Cancer Research 54, 6106 (1994)), and 4-pyridyl-2-arylpyrimidines (Proc. Natl. Acad. Sci. USA. 92, 2558 (1995)).
However, as far as the present inventors know, compounds which have a structure in which an aryl group or heteroaryl group is bonded to position 4 of the quinoline backbone or quinazoline backbone via one oxygen atom, sulfur atom or carbon atom and which have a PDGF receptor autophosphorylation inhibitory activity are not known.
Furthermore, as to previously known quinoline derivatives, {4-[(7-chloro-4-quinolinyl)oxy]phenyl}(4-fluorophenyl)methanone is described in Publication of Examined Japanese Patent Application No. 89/246263. This known compound is used as a fungicide, and there are no reports as to its PDGF receptor autophosphorylation inhibitory activity.
Furthermore, 4-arylquinoline derivatives are described in J. Med. Chem. 14, 1060 (1971), Acta Chim. Hung 112, 241 (1983), Publication of Examined Japanese Patent Application No. 88/51375, German Patent No. 3101544, Publication of Examined Japanese Patent Application No. 89/246263, and U.S. Pat. No. 3,936,461. These known compounds are each reported as an antihypertensive agent or intermediate for its production, agent to prevent harmful organisms (preservative), plant growth control agent, fungicide or anti-angina agent, respectively, and there are no reports as to their PDGF receptor autophosphorylation inhibitory activity.
Consequently, the development of novel compounds having the PDGF receptor autophosphorylation inhibitory activity would be of great industrial benefit.
A major objective of the present invention is to provide novel compounds having the PDGF receptor autophosphorylation inhibitory activity.